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Jung-Hua Yeh^*,, Shu-Ching Hsu^,, Shou-Hwa Han^*, and Ming-Zong Lai^*,,

From the ^* Graduate Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 11217, Taiwan; the Institute of Molecular Biology, Academia Sinica, Nankang, Taipei 11529, Taiwan; and the Graduate Institute of Microbiology, National Taiwan University School of Medicine, Taipei 10018, Taiwan

Fas and Fas-associated death domain (FADD) play a critical role in the homeostasis of different cell types. The regulation of Fas and FADD-mediated cell death is pivotal to many physiological functions. The activation of T lymphocytes by concanavalin A (Con A) inhibited Fas-mediated cell death. We identified that among the several activation signals downstream of Con A stimulation, mitogen-activated protein (MAP) kinase kinase (MKK) was the major kinase pathway that antagonized Fas-triggered cell death. MKK1 suppressed FADD- but not caspase-3– induced apoptosis, indicating that antagonism occurred early along the Fas-initiated apoptotic cascade. We further demonstrated that activation of MKK1 led to expression of FLIP, a specific inhibitor of FADD. MKK1 inhibition of FADD-induced cell death was abrogated if induction of FLIP was prevented, indicating that FLIP mediates MKK1 suppression of FADD-mediated apoptosis. Our results illustrate a general mechanism by which activation of MAP kinase attenuates apoptotic signals initiated by death receptors in normal and transformed cells.

Key Words: mitogen-activated protein kinase kinase • Fas-associated death domain protein • Fas • FLIP • apoptosis

This project was supported by grant DOH86-HR-508 from the Department of Health, grant NSC 86-2316-B001-012 M30 from the National Science Council, and a grant from Academia Sinica.

Abbreviations used: DR, death receptor; FADD, Fas-associated death domain protein; FLICE, FADD-like ICE; FLIP, FLICE-inhibitory protein; ICE, IL-1β–converting enzyme; MAPK, mitogen-activated protein kinase; MKK, MAPK kinase; nt, nucleotide(s); PI, propidium iodide; RT, reverse transcription.

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• Perlman, H., Pagliari, L. J., Georganas, C., Mano, T., Walsh, K., Pope, R. M. (1999). Flice-Inhibitory Protein Expression during Macrophage Differentiation Confers Resistance to FAS-Mediated Apoptosis. JEM 190: 1679-1688 [Abstract] [Full Text]  

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